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Updated: Jun 10, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Glutamine-mediated protection from neuronal cell death depends on mitochondrial activity
E V Stelmashook1, E R Lozier, E S Goryacheva
1Institute of Neurology, Department of Brain Research, Russian Academy of Medical Sciences, 105064 Moscow, Russia.
Abstract:
The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival.
Insights
Glutamine can worsen neuronal death by stimulating glutamate receptors when mitochondria are impaired. However, it supports neuronal survival by providing energy when mitochondria are functional.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondria play a critical role in neuronal survival.
- Metabolic disturbances can lead to neuronal death.
- Intracellular calcium and glutamine are implicated in cell death pathways.
Purpose of the Study:
- To investigate the role of mitochondria in neuronal death induced by metabolic factors.
- To explore the involvement of intracellular calcium and glutamine in both mitochondria-dependent and independent cell death.
- To understand how glutamine affects neuronal survival under varying metabolic conditions.
Main Methods:
- Utilized cultured cerebellar granule neurons (CGNs).
- Applied metabolic effectors like rotenone (mitochondrial complex I inhibitor) and ouabain (Na/K-ATPase inhibitor).
- Manipulated glucose availability and glutamine levels; blocked ionotropic glutamate receptors and used NMDA.
Main Results:
- Rotenone-induced neuronal death was preceded by increased intracellular calcium ([Ca(2+)](i)) and potentiated by glutamine.
- Ouabain induced cell death only without glucose, an effect prevented by glutamine.
- Glutamate receptor activation contributed to rotenone and ouabain toxicity, with NMDA exacerbating cell death under hypoglycemia, an effect mitigated by glutamine.
Conclusions:
- Glutamine enhances glutamate-dependent neuronal damage when mitochondrial respiration is compromised.
- When mitochondria are functional, glutamine serves as an alternative substrate, supporting cellular energy and promoting neuronal survival.
